Triple-Combination Blood Pressure Pill Reduces Ischemic Stroke Risk, With Craig Anderson, PhD

GMRx2, a combination of 3 low-dose blood pressure medications in a single pill, has proven its efficacy in substantially reducing stroke risk in patients with intracerebral hemorrhage (ICH), according to data from the TRIDENT phase 3 trial.1

Intracerebral hemorrhage is the direct contributor to a disproportionate percentage of stroke-related morbidity and mortality. Among its primary causes is chronic hypertension, another famously under-managed condition affecting a substantial proportion of the population. Blood pressure reduction is therefore a cornerstone of modern ICH treatment and prevention of further stroke.2

“One of the problems we’ve had in blood pressure control for secondary prevention after stroke is just achieving the targets, whether that’s <140 or, more stringently, <130,” Craig Anderson, PhD, professor of neurology and epidemiology, director of the Brain Health Program at the George Institute, and principal investigator, told HCPLive in an exclusive interview. “It’s very challenging to do that in clinical practice – most patients will require multiple drugs and that causes problems with medication adherence. Our trial shows that achieving blood pressure <130 is achievable, and that the triple pill approach can do it very effectively compared to standard treatment.”

The Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT) was a multicenter, international, double-blinded, placebo-controlled, parallel-group, randomized controlled trial comparing more intensive blood pressure control through the “triple pill” GMRx2 on top of standard care to treatment with matched placebo. Anderson and colleagues aimed to assess the triple pill’s efficacy and safety in preventing recurrent ischemic strokes in patients with a history of ICH and high, normal, or low-grade hypertension. The trial was conducted across 58 locations worldwide.2

Patients were eligible for inclusion if they had a history of primary ICH confirmed via imaging and an average of 2 resting systolic blood pressure (SBP) levels measured 5 minutes apart in the range 130-160 mmHg, among other criteria. Patients taking an ACE inhibitor which could not be switched to a study alternative or who had severe hepatic impairment, significant hyperkalemia, or hyponatremia, among other criteria, were excluded.2

Enrolled patients were randomly assigned to receive either GMRx2 – a combination of telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg – or placebo, both of which were daily pills taken orally for an average of 72 months. The study’s primary outcome was time to first occurrence of recurrent stroke, whether ischemic or hemorrhagic. Secondary outcomes included time to first occurrence of recurrent ICH, mortality, major adverse cardiovascular events, and change in SBP, among others.2

A total of 1670 patients were ultimately enrolled, all of whom had SBP within 130-160 mmHg. Over the course of the study, stroke occurred in 4.6% of patients receiving GMRx2 versus 7.4% receiving placebo. Major adverse cardiovascular events occurred in 6.6% of GMRx2 recipients compared to 9.8% of placebo recipients, resulting in a 33% reduction. Additionally, Anderson and colleagues noted a 9 mmHg greater SBP reduction in the GMRx2 arm.1

“The important thing about TRIDENT was the additional benefit that was achieved by most of the patients already on a treatment,” Anderson told HCPLive. “Most people were on multiple drugs, and most people were within clinicians’ understanding of good control. And even with that, the addition of GMRx2 allowed them to achieve this amazingly extra benefit.”

Editors’ Note: Anderson reports disclosures with the National Health and Medical Research Council of Australia, the Medical Research Council of the UK, Takeda, Credit, Genesis, and Penumbra, Inc.

References

1. Anderson C, Chow C, de Silva H, et al. Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage. NEJM. 2026;394(16):1571-1582. doi:10.1056/NEJMoa2515043

2. Schrag M, Kirshner H. Management of Intracerebral Hemorrhage: JACC Focus Seminar. J Am Coll Cardiol. 2020;75(15):1819-1831. doi:10.1016/j.jacc.2019.10.066

3. The George Institute. Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT). ClinicalTrials.gov Identifier: NCT02699645. Updated September 12, 2025. Accessed April 22, 2026. https://clinicaltrials.gov/study/NCT02699645